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Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress.

ABSTRACT: Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders. While it is well known that acute environmental stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive epigenetic modification that is highly enriched in neurons and is associated with active neuronal transcription. Recently, we reported a genome-wide disruption of hippocampal 5hmC in male mice following acute stress that was correlated to altered transcript levels of genes in known stress related pathways. Since sex-specific endocrine mechanisms respond to environmental stimulus by altering the neuronal epigenome, we examined the genome-wide profile of hippocampal 5hmC in female mice following exposure to acute stress and identified 363 differentially hydroxymethylated regions (DhMRs) linked to known (e.g., Nr3c1 and Ntrk2) and potentially novel genes associated with stress response and psychiatric disorders. Integration of hippocampal expression data from the same female mice found stress-related hydroxymethylation correlated to altered transcript levels. Finally, characterization of stress-induced sex-specific 5hmC profiles in the hippocampus revealed 778 sex-specific acute stress-induced DhMRs some of which were correlated to altered transcript levels that produce sex-specific isoforms in response to stress. Together, the alterations in 5hmC presented here provide a possible molecular mechanism for the adaptive sex-specific response to stress that may augment the design of novel therapeutic agents that will have optimal effectiveness in each sex.

SUBMITTER: Papale LA

PROVIDER: S-EPMC5103857 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress.

Papale Ligia A LA Li Sisi S Madrid Andy A Zhang Qi Q Chen Li L Chopra Pankaj P Jin Peng P Keleş Sündüz S Alisch Reid S RS

Neurobiology of disease 20160826

Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders. While it is well known that acute environmental stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive epigenetic modification that is highly enriched in neurons and is associated with active neuronal transcription. Recently, we reported a genome-wide disrup ...[more]

PMID: 27576189

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Project description:Dysregulations of the central serotoninergic system have been implicated in several psychopathologies, characterized by different susceptibility between males and females. We took advantage of tryptophan hydroxylase 2 (TPH2) deficient rats, lacking serotonin specifically in the brain, to investigate whether a vulnerable genotype can be associated with alterations of neuronal plasticity from the early stage of maturation of the brain until adulthood. We found a significant increase, in both gene and protein expression, of the neurotrophin brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) of adult TPH2-deficient (TPH2-/-) male and female rats in comparison to wild type (TPH2+/+) counterparts. Interestingly, a development-specific pattern was observed during early postnatal life: whereas the increase in Bdnf expression, mainly driven by the modulation of Bdnf isoform IV was clearly visible after weaning at postnatal day (pnd) 30 in both sexes of TPH2-/- in comparison to TPH2+/+ rats, at early stages (pnd1 and pnd10) Bdnf expression levels did not differ between the genotypes, or even were downregulated in male TPH2-/- animals at pnd10. Moreover, to establish if hyposerotonergia may influence the response to a challenging situation, we exposed adult rats to an acute stress. Although the pattern of corticosterone release was similar between the genotypes, neuronal activation in response to stress, quantified by the expression of the immediate early genes activity regulated cytoskeleton associated protein (Arc) and Fos Proto-Oncogene (cFos), was blunted in both sexes of animals lacking brain serotonin. Interestingly, although upregulation of Bdnf mRNA levels after stress was observed in both genotypes, it was less pronounced in TPH2-/- in comparison to TPH2+/+ rats. In summary, our results demonstrated that serotonin deficiency affects neuroplastic mechanisms following a specific temporal pattern and influences the response to an acute stress.

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Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress.

Publications

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress.

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